title: Mesenchymal stem cells from osteoporotic patients feature impaired signal transduction but sustained osteoinduction in response to BMP-2 stimulation.
abstract: Osteoporotic fractures show reduced callus formation and delayed bone healing. Cellular sources of fracture healing are mesenchymal stem cells (MSC) that differentiate into osteoblasts by stimulation with osteoinductive cytokines, such as BMP-2. We hypothesized that impaired signal transduction and reduced osteogenic differentiation capacity in response to BMP-2 may underlie the delayed fracture healing. Therefore, MSC were isolated from femoral heads of healthy and osteoporotic patients. Grouping was carried out by bone mineral densitometry in an age-matched manner. MSC were stimulated with BMP-2. Signal transduction was assessed by western blotting of pSMAD1/5/8 and pERK1/2 as well as by quantitative RT-PCR of Runx-2, Dlx5, and Osteocalcin. Osteogenic differentiation was assessed by quantifying Alizarin Red staining. Osteoporotic MSC featured an accurate phosphorylation pattern of SMAD1/5/8 but a significantly reduced activation of ERK1/2 by BMP-2 stimulation. Furthermore, osteoporotic MSC showed significantly reduced basal expression levels of Runx-2 and Dlx5. However, Runx-2, Dlx5, and Osteocalcin expression showed adequate up-regulation due to BMP-2 stimulation. The global osteogenic differentiation in standard osteogenic differentiation media was reduced in osteoporotic MSC. Nevertheless, osteoporotic MSC were shown to feature an adequate induction of osteogenic differentiation due to BMP-2 stimulation. Taken together, we here demonstrate osteoporosis associated alterations in BMP-2 signaling but sustained specific osteogenic differentiation capacity in response to BMP-2. Therefore, BMP-2 may represent a promising therapeutic agent for the treatment of fractures in osteoporotic patients.
authors.affiliation: Department of Surgery, Experimental Surgery and Regenerative Medicine, University of Munich (LMU), Nußbaumstr. 20, D-80336 Munich, Germany. Electronic address: Christian.Prall@med.uni-muenchen.de.
authors.forename: Wolf Christian
authors.initials: WC
authors.lastname: Prall
authors.forename: Florian
authors.initials: F
authors.lastname: Haasters
authors.forename: Jostein
authors.initials: J
authors.lastname: Heggebö
authors.forename: Hans
authors.initials: H
authors.lastname: Polzer
authors.forename: Christina
authors.initials: C
authors.lastname: Schwarz
authors.forename: Christoph
authors.initials: C
authors.lastname: Gassner
authors.forename: Stefan
authors.initials: S
authors.lastname: Grote
authors.forename: David
authors.initials: D
authors.lastname: Anz
authors.forename: Marcus
authors.initials: M
authors.lastname: Jäger
authors.forename: Wolf
authors.initials: W
authors.lastname: Mutschler
authors.forename: Matthias
authors.initials: M
authors.lastname: Schieker
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology* / Q000627:therapeutic use; D002469:Cell Separation; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010012:Osteogenesis; D010024:Osteoporosis / Q000628:therapy*; D010766:Phosphorylation; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; C100596:DLX5 protein, human; D018398:Homeodomain Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D014157:Transcription Factors; D048052:Mitogen-Activated Protein Kinase 3
keywords: BMP-2; Mesenchymal stem cells; Osteogenic differentiation; Osteoporosis; Signal transduction